CILEST 250/ 35 MICROGRAM TABLETS

Main information

  • Trade name:
  • CILEST 250/ 35 MICROGRAM TABLETS
  • Dosage:
  • 250/ 35 Microgram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CILEST 250/35 MICROGRAM TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/217/001
  • Authorization date:
  • 03-07-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Cilest250/35microgramTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains250microgramsnorgestimateand35microgramsethinylestradiol.

Excipient:containslactoseanhydrous

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Tablet

ProductimportedfromtheUK:

Adarkblue,flat,bevel-edgedtabletengraved“C”over“250”onbothfaces.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Hormonalcontraception.

4.2Posologyandmethodofadministration

Fororaladministration.

Adults:

Whenusedperfectly,withoutmissinganypills,thechanceofbecomingpregnantislessthan1%(i.e.<1pregnancyper

100womenintheirfirstyearofuse).Typicalfailureratesareactually5%inthefirstyear.Thechanceofbecoming

pregnantincreaseswitheachmissedpillduringamenstrualcycle.

BeforestartingCilest,athoroughgeneralmedicalandgynaecologicalexamination(includingthebreastsanda

cytologicalsmearofthecervix)ifappropriateshouldbecarriedoutandthefamilymedicalhistorycarefullynoted.

Disturbancesoftheclottingmechanismsshouldberuledoutifanymembersofthefamilyhavesufferedfromthrombo-

embolicdiseases(egdeepveinthrombosis,stroke,myocardialinfarction)atayoungage.

Pregnancymustbeexcludedideallybyapregnancytest.

Asaprecaution,thoroughmedicalexaminationsshouldbeconductedatapproximatelysixmonthintervalsduringuse

ofthetablets.

Children:

SafetyandefficacyofCilestTabletshaveonlybeenestablishedinwomenofreproductiveage.

Elderly:

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-Firstcycle

Tablet-takingfromthefirstpackofCilestisstartedonthe1stdayofthemenstrualcycle,iethefirstdayofmenstrual

bleeding.Ifmenstruationhasalreadybegun,Cilestmaybecommenceduptoday5ofthemenstrualperiod,provided

additionalcontraceptiveprecautionsaretakenforthefirst7daysoftablettaking.

Onetabletistobetakenataroundthesametimeofdayoneachof21consecutivedaysfollowedbyatablet-free

intervalof7days,duringwhichawithdrawalbleedingoccurs.

-Subsequentcycles

Tablet-takingfromthenextpackofCilestiscontinuedafterthe7-dayinterval,beginningonthesamedayoftheweek

asthefirstpack.

-Changingfromanotheroralcontraceptive

-Changingfroma21daypilltoCilest:

Alltabletsintheoldpackshouldbefinished.ThefirstCilesttabletistakenthenextdayi.e.nogapisleftbetween

takingtabletsnordoesthepatientneedtowaitforherperiodtobegin.Additionalcontraceptiveprecautionsarenot

required.ThepatientwillnothaveaperioduntiltheendofthefirstCilestpack,butthisisnotharmful,nordoesit

matterifsheexperiencessomebleedingontablet-takingdays.

-Changingfromacombinedeverydaypill(28daytablets)toCilest:

Cilestshouldbestartedaftertakingthelastactivetabletfromthe'EverydayPill'pack(ieaftertaking21tablets).The

firstCilesttabletistakenthenextday,ienogapisleftbetweentakingtabletsnordoesthepatientneedtowaitforher

periodtobegin.Additionalcontraceptiveprecautionsarenotrequired.Remainingtabletsfromtheeveryday(ED)pack

shouldbediscarded.

ThepatientwillnothaveaperioduntiltheendofthefirstCilestpack,butthisisnotharmful,nordoesitmatterifshe

experiencessomebleedingontablet-takingdays.

-Changingfromaprogestogen-onlypill(POPorminipill)toCilest:

ThefirstCilesttabletshouldbetakenonthefirstdayoftheperiod,evenifthepatienthasalreadytakenaminipillon

thatday.Additionalcontraceptiveprecautionsarenotrequired.Alltheremainingprogestogen-onlypillsinthemini

pillpackshouldbediscarded.

Ifthepatientistakingaminipill,thenshemaynotalwayshaveaperiod,especiallywhensheisbreast-feeding.The

firstCilesttabletshouldbetakenonthedayafterstoppingtheminipill.Allremainingpillsintheminipillpacketmust

bediscarded.Additionalcontraceptiveprecautionsmustbetakenforthefirst7days.

-Irregulartablet-taking

Ifapatientmissesoneortwotabletssheshouldtakethemissedtabletassoonaspossibleandtakethenexttabletatthe

usualtime(thismaymeantakingtwotabletsatonce).Sheshouldcontinuetakingthetabletsasusualthereafter,butif

sheismorethan12hourslatetakinghertabletsheshouldabstainfromsexualintercourseoruseadditional,non-

hormonalcontraception(exceptrhythmortemperaturemethod)untilshehastaken7tabletsinarow.Ifapatient

missesthreeormoretablets,sheshouldtakethefirstmissedtabletassoonas

possibleandtakethenexttabletattheusualtime(thismaymeantakingtwotabletsatonce).Sheshouldcontinue

takingthetabletsasusualthereafter,butshouldabstainfromsexualintercourseoruseaddition,non-hormonal

contraception(exceptrhythmortemperaturemethod)untilshehastaken7tabletsinarow.

Ifthetabletsweremissedinthethirdweek,thepatientshouldcontinuetakingthetabletsasusualthereafteruntilthe

packisfinishedandthenstartthenextpackimmediatelywithoutwaitingforawithdrawalbleed.Ifthetablet-free

intervalisavoidedinthiswayshedoesnotneedtouseemergencycontraception.

Ifthetabletsweremissedinthefirstweek(effectivelyextendingthetablet-freeinterval)thepatientmaywishto

considertheuseofemergencycontraceptionifappropriate.

-Postpartum

Normally,afteradelivery,Cilestshouldbestartedafterthefirstnormalmenstrualcycle.

Ifimmediatereliablecontraceptionisrequiredformedicalreasons,medicationwithCilestmaybeinitiatedafterday

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-Postmiscarriage

Followingamiscarriageat,orbefore,20weeksgestation,oralcontraceptioncanbestartedimmediately(day2butno

laterthan5)forimmediatecover.Ovulationmayoccurwithin10daysofmiscarriage.

NB:Whenoralcontraceptivesareadministeredintheimmediatepostpartum/postmiscarriageperiod,theincreasedrisk

ofthrombo-embolicdiseasemustbeconsidered.

-Absenceofwithdrawalbleeding

If,inexceptionalcases,withdrawalbleedingfailstooccur,pregnancymustberuledoutbeforetheuseofCilestis

continued.

-Procedureintheeventofirregularbleeding

Breakthroughbleedingandspottingaresometimesencountered,primarilyduringthefirstthreemonthsofuse,and

usuallyceasespontaneously.Thewoman,therefore,shouldcontinuetouseCilestevenifirregularbleedingoccurs.

Shouldbreak-throughbleedingpersistorrecur,appropriatediagnosticmeasurestoexcludeanorganiccauseare

indicated,andmayincludecurettage.

Thisalsoappliesinthecaseofspottingwhichoccursatirregularintervalsinseveralconsecutivecyclesorwhich

occursforthefirsttimeafterlonguseofCilest.

-Gastro-intestinalupset

Vomitingordiarrhoeamayreducetheefficacyoforalcontraceptivesbypreventingfullabsorption.Tablet-takingfrom

thecurrentpackshouldbecontinued.Additionalnon-hormonalmethodsofcontraception(excepttherhythmor

temperaturemethods)shouldbeusedduringthegastro-intestinalupsetandfor7daysfollowingtheupset.Ifthese7

daysoverruntheendofapack,thenextpackshouldbestartedwithoutabreak.Inthissituation,awithdrawalbleed

shouldnotbeexpecteduntiltheendofthesecondpack.Ifthepatientdoesnothaveawithdrawalbleedduringthe

tablet-freeintervalfollowingtheendofthesecondpack,the

possibilityofpregnancymustberuledoutbeforeresumingwiththenextpack.Othermethodsofcontraceptionshould

beconsideredifthegastro-intestinaldisorderislikelytobeprolonged(iegreaterthan12hours).

4.3Contraindications

1.Confirmedorsuspectedpregnancy

2.Patientsbreastfeedinginfants.

3.Acuteorchronicliverdiseasewithabnormalliverfunction,jaundiceorpersistentpruritusduringaprevious

pregnancy,Dubin-Johnsonsyndrome,Rotorsyndrome,porphyria.

4.Activeviralhepatitis

5.Severecirrhosisoftheliver

6.Existingorpreviousarterialorvenousthromboticorembolicprocessesorconditionswhichpredisposetothem,eg

disordersoftheclottingprocesses,coronaryarterydisease,cerebrovasculardisease,valvularheartdiseaseandatrial

fibrillation.Multipleriskfactorsforarterialcardiovasculardisease(suchasolderage,smoking,diabetesand

hypertension).

7.Sickle-cellanaemia.

8.Currentorpreviousknownorsuspectedoestrogen-dependentneoplasia,egpreviousorexistinglivertumours,

cancerofthebreastorendometrium.

9.Severediabetesmellituswithvascularchanges(includingretinopathy,nephropathyorneuropathy),or>20years'

duration.

10.Disordersoflipidmetabolism.(See4.4PrecautionsandWarnings).

11.Pemphigoidgestationis.

12.Manifestationordeteriorationofotosclerosisduringpregnancy.

13.Undiagnosedvaginalbleeding.

14.HypersensitivitytoanyofthecomponentsofCilest.

15.Cholelithiasis.

16.Systemiclupuserythematosusorahistoryofthiscondition.

17.Migrainewithfocalaura,orwithoutfocalaurainpatientsaged35yearsandover.

18.Severehypertension(persistentsystolicvaluesof160orpersistentdiastolicvalues100mmHg).

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20.Knownthrombogenicmutations(e.g.FactorVLeiden;Prothrombinmutation;ProteinS,ProteinC,and

Antithrombindeficiencies).

4.4Specialwarningsandprecautionsforuse

ReasonsforimmediatediscontinuationofmedicationwithCilest.

1.Suspectedorconfirmedsymptomsorsignsofthrombophlebitisorthrombo-embolicevents(egunusualpainsinor

swellingofthelegs).

2.Feelingofpainandtightnessinthechest(stabbingpainsonbreathingorcoughingfornoapparentreason).

3.Occurrenceforthefirsttime,orexacerbationofmigrainousheadachesoranincreasedfrequencyofunusuallysevere

headaches.

4.Suddendisturbancesofvisionorhearing.

5.Sixweeksbeforeelectivesurgeryandduringprolongedimmobilisationegafteraccidents,surgery.

6.Onsetofjaundice,hepatitis,itchingofthewholebody.

7.Onsetorworseningofepilepsy.

8.Significantriseinbloodpressure.

9.Onsetofseveredepression.

10.Severeupperabdominalpainorliverenlargement.

11.Pregnancy.

Patientswiththefollowingconditionsshouldonlyusetheoralcontraceptivepillafterdetaileddiscussionwith

theirGeneralPractitioner.Patientswiththeseconditionsrequirestrictmedicalsupervisionduringmedication:

1.Diabetesmellitus.

2.Hypertension(persistentsystolicvaluesof140–159orpersistentdiastolicvaluesof90–99mmHg).

3.Varicoseveins.

4.Otosclerosis.

5.Multiplesclerosis.

6.Epilepsy.

7.Tetany.

8.Sydenham'schorea.

9.Renaldysfunction.

10.Familyhistoryofbreastcancerorpasthistoryofbreastnodules.

11.Fibrocysticdiseaseofthebreast.

12.Asthma.

13.Historyofclinicaldepression.

14.Systemiclupuserythematosus.

15.Uterinemyoma.

16.Migraine.

17.Endometriosis.

18.Conditionsimplicatedinanincreasedriskofdevelopingvenousthrombo-emboliccomplications,egsevere

varicoseveinsorprolongedimmobilisationormajorsurgery.Disordersofcoagulation.Presenceofanyriskfactorfor

arterialdisease,suchassmoking,hyperlipidemia,hypertensionorobesity.Withregardstosmoking,theriskof

cardiovascularcomplicationsincreaseswithageandthenumberofcigarettessmoked.

19.Otherconditionsassociatedwithanincreasedriskofcirculatorydiseasesuchaslatentorovertcardiacfailure,renal

dysfunctionorahistoryoftheseconditions.

20.Ahistoryofcholelithiasis.

21.Concurrentadministrationofrifampicinoranyotherproductknowntoaffectliverenzymes(seesection4.5).

Deteriorationinanyoftheaboveconditionsmayindicatethatuseoftheoralcontraceptiveshouldbe

discontinued.

OralcontraceptivesDONOTprotectagainstHIVinfections(AIDS)oranyothersexuallytransmitteddisease.

Incaseofundiagnosed,persistentorrecurrentabnormalvaginalbleeding,appropriatemeasuresshouldbeconductedto

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Theuseofcombinedoralcontraceptivescarriesanincreasedriskofvenousthrombo-embolism(VTE)comparedwith

nouse.TheexcessriskofVTEishighestduringthefirstyearawomaneverusesacombinedoralcontraceptive.This

increasedriskislessthantheriskofVTEassociatedwithpregnancy,whichisestimatedas60casesperhundred

thousandpregnancies.VTEisfatalin1to2%ofthesecases.

ItisnotknownhowCilestinfluencestheriskofVTEcomparedwithotheroralcontraceptives.Thephysicianshould

bealerttotheearliestmanifestationsofvenousandarterialthrombo-embolicdisease,iemyocardialinfarction,

pulmonaryembolism,thrombophlebitis,strokeorretinalthrombosis.Shouldanyoftheseoccurorbesuspected,Cilest

shouldbediscontinuedimmediately.Thephysicianshouldbearinmindthepossibilityofvascularaccidentsoccurring

andthattheremaynotbefullrecoveryfromsuchdisordersandtheymaybefatal.

Therelativeriskofarterialthromboses(egstroke,myocardialinfarction)isincreasedbythepresenceofother

predisposingfactorssuchas:

a)cigarettesmoking

b)hypercholesterolaemia

c)obesity

d)diabetes

e)historyofpre-eclamptictoxaemia

f)increasingage

Aftertheageof35years,thephysicianandpatientsshouldcarefullyreassesstherisk/benefitratioofusingcombined

oralcontraceptivesasopposedtoalternativemethodsofcontraception.

Oralcontraceptivesmaycauseadecreaseinglucosetolerance.Thiseffecthasbeenshowntobedirectlyrelatedto

oestrogendose.Additionally,progestogensmayincreaseinsulinsecretionandcreateinsulinresistance,thiseffect

varieswithdifferentprogestationalagents.However,inthenon-diabeticwoman,oralcontraceptivesappeartohaveno

effectonfastingbloodglucose.Becauseofthesedemonstratedeffects,pre-diabeticanddiabeticwomeninparticular

shouldbecarefullymonitoredwhiletakingoralcontraceptives.

Asmallproportionofwomenwillhavepersistenthypertriglyceridemiawhileonthepill.Changesinserum

triglycerides,cholesterolandlipoproteinlevelshavebeenreportedinusersoforalcontraceptives.

Theonsetorexacerbationofmigraineordevelopmentofheadachewithanewpatternwhichisrecurrent,persistentor

severerequiresdiscontinuationoforalcontraceptivesandevaluationofthecause.

Anincreaseinbloodpressurehasbeenreportedinwomentakingoralcontraceptives.Elevatedbloodpressureusually

returnstonormalafterdiscontinuationoforalcontraceptives.

Somewomenmayexperienceamenorrhoeaoroligomenorrhoeaafterdiscontinuationoforal

contraceptives,especiallywhentheseconditionsexistedpriortouse.Womenshouldbeinformedofthispossibility.

Inrarecasesbenignand,inevenrarercases,malignantlivertumoursleadinginisolatedcasestolife-threateningintra-

abdominalhaemorrhagehavebeenobservedaftertheuseofhormonalsubstancessuchasthosecontainedinCilest.If

severeupperabdominalcomplaints,liverenlargementorsignsofintra-abdominalhaemorrhageoccur,thepossibilityof

alivertumourshouldbeincludedinthedifferentialdiagnosis.

Atleastthreemonthsshouldelapseafterliverfunctiontestshavereturnedtonormalfollowinganyhepatitisbefore

administrationoftheoralcontraceptivepill.

Chloasmamayoccasionallyoccur,especiallyinwomenwithahistoryofchloasmagravidarum.Womenwitha

tendencytochloasmashouldavoidexposuretothesunorultravioletradiationwhiletakingthispreparation.Chloasma

isoftennotfullyreversible.

Studiesinanimalshaveindicatedthatadministrationofveryhighdosesofoestrogensand/orprogestogenswillinduce

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Numerousepidemiologicalstudieshavebeenreportedontheriskofovarian,endometrial,cervicalandbreastcancerin

womenusingcombinedoralcontraceptives.Theevidenceisclearthatcombinedoralcontraceptivesoffersubstantial

protectionagainstbothovarianandendometrialcancer.

Whilethereareconflictingreports,moststudiessuggestthatuseoforalcontraceptivesisnotassociatedwithanoverall

increaseintheriskofdevelopingbreastcancer.Somestudieshavereportedanincreasedrelativeriskofdeveloping

breastcancer,particularlyatayoungerage.Thisincreasedrelativeriskhasbeenreportedtoberelatedtodurationof

use.

Ameta-analysisof54epidemiologicalstudiesreportsthatwomenwhoarecurrentlyusingcombinedoral

contraceptivesorhaveusedtheminthepast10yearsareataslightlyincreasedriskofhavingbreastcancerdiagnosed,

althoughtheadditionalcancerstendtobelocalizedtothebreast.Itisnotpossibletoinferfromthisdatawhetherthe

patternsofriskobservedareduetoanearlierdiagnosisofbreastcancerinever-users,thebiologicaleffectsof

hormonalcontraceptives,oracombinationofbothfactors.Thismeta-analysisalsosuggeststhattheageatwhich

womendiscontinuetheuseofcombinedoralcontraceptivesisanimportantriskfactorforbreastcancer;theolderthe

ageatstopping,themorebreastcancersarediagnosed.Durationofusewasconsideredlessimportant.

Theresultsofrecentstudiesinhumanbeingssuggestthatthereisasmallbutstatisticallyincreasedincidenceofbreast

cancerinwomenwhohavebeentreatedwithoestrogens.Thepossibleincreaseinriskofbreastcancershouldbe

discussedwithwomenandweighedagainstthebenefitsofcombinedoralcontraceptives.

Anincreasedriskofcervicalcancerinlongtermusersofcombinedoralcontraceptiveshasbeenreportedinsome

studies,buttherecontinuestobecontroversyabouttheextenttowhich

thisisattributabletotheconfoundingeffectsofsexualbehaviourandotherfactors.

Allwomen,inparticularthoseover35years,shouldhaveregularbreastexaminationswhileonthepill.

HerbalpreparationscontainingStJohn'sWort(Hypericumperforatum)shouldnotbeusedwhiletakingCilestdueto

theriskofdecreasedplasmaconcentrationsandreducedclinicaleffectsofCilest(seeSection4.5Interactions).

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Themetabolismofhormonalcontraceptivesmaybeinfluencedbyvariousdrugs.Ofpotentialclinicalimportanceare

drugsthatcausetheinductionofenzymesthatareresponsibleforthedegradationofestrogensandprogestins,and

drugsthatinterruptentero-hepaticrecirculationofestrogen(e.g.certainantibiotics).

Themajortargetforenzymeinducersisthehepaticmicrosomalestrogen-2-hydroxylase(cytochromeP4503A4).

Reducedcontraceptiveefficacyhasbeendocumentedwithconcomitantuseofhormonalcontraceptivesandrifampicin.

Literaturereportsthathormonalcontraceptivesinteractwithsomeanti-retroviralagents,modafinil,topiramate,

barbiturates,griseofulvin,phenylbutazone,phenytoinsodium,carbamazepineandbosentan.Interactionswith

medicinesthatincreaseclearanceofsexhormonesmayresultinbreakthroughbleedingandpregnancy.Theefficacyof

Cilestinuserswhoarereceivinglong-termtreatmentwithahepaticenzyme-inducingagenthasnotbeenestablished.

Therefore,inuserstakinghepaticenzyme-inducingdrugs,thisinformationshouldbeconsideredinchoosinga

contraceptivemethod.

ApossibleinteractionhasbeensuggestedwithhormonalcontraceptivesandtheherbalsupplementSt.John'swort

basedonsomereportsoforalcontraceptiveusersexperiencingbreakthroughbleedingshortlyafterstartingSt.John's

wort.PregnancieshavebeenreportedbyusersofcombinedhormonalcontraceptiveswhoalsousedsomeformofSt.

John'swort.

Someproteaseinhibitorsandsomeanti-retroviralagentshavebeenfoundtoeitherincrease(e.g.Indinavir)ordecrease

(e.g.Ritonavir)circulatinglevelsofcombinationhormonalcontraceptives.

Anothertypeofinteractionistheimpairmentoftheenterohepaticrecirculationofestrogensthatmayresultinhastened

eliminationandimpairedeffectiveness.Thismaybeduetoabsorptionofbiliaryestrogenconjugates(e.g.by

cholestyramine)ortoinsufficientcleavageoftheconjuatebyintestinalbacteria,thelatterbeingobservedafter

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Womenreceivingshortcoursesofenzymeinducersorbroadspectrumantibioticsshouldtakeadditional,non-hormonal

(exceptrhythmortemperaturemethod)contraceptiveprecautionsduringthetimeofconcurrentmedicationandfor7

daysafterwards.Ifthese7daysoverruntheendofthepack,thenextpackshouldbestartedwithoutabreak.Inthis

situation,awithdrawalbleedshouldnotbeexpecteduntiltheendofthesecondpack.Ifthepatientdoesnothavea

withdrawalbleedduringthetablet-freeintervalfollowingtheendofthesecondpack,thepossibilityofpregnancymust

beruledoutbeforeresumingwiththenextpack.With

rifampicin,additionalcontraceptiveprecautionsshouldbecontinuedfor4weeksaftertreatmentstops,evenifonlya

shortcoursewasadministered.

Therequirementfororalantidiabeticsorinsulincanchangeasaresultoftheeffectonglucosetolerance.

Theuseoforalcontraceptivesmayinfluencetheresultsofcertainlaboratorytestsincludingbiochemicalparametersof

liver,thyroid,adrenal,andrenalfunction,plasmalevelsofcarrierproteinsandlipid/lipoproteinfractions,parametersof

carbohydratemetabolismandparametersofcoagulationandfibrinolysis.Laboratorystaffshouldthereforebeinformed

aboutoralcontraceptiveusewhenlaboratorytestsarerequested.

4.6Fertility,pregnancyandlactation

IfpregnancyoccursduringmedicationwithCilest,thepreparationshouldbewithdrawnimmediately.

Anincreasedriskofcongenitalabnormalities,includingheartdefectsandlimbdefects,hasbeenreportedfollowingthe

useofsexhormonesincludingoralcontraceptivesinpregnancy.

TheuseofCilestduringlactationmayleadtoareductioninthevolumeofmilkproducedandtoachangeinits

composition.Minuteamountsoftheactivesubstancesareexcretedwiththemilk.

Cilestiscontraindicatedduringbreast-feeding.Adecisionmustbemadewhethertodiscontinuebreast-feedingorto

discontinue/abstainfromCilest.

4.7Effectsonabilitytodriveandusemachines

Notapplicable.

4.8Undesirableeffects

Thefollowingadversereactionshavebeenassociatedwiththeuseofnorgestimate/ethinylestradiol(seeSection4.4.

SpecialWarningsandPrecautionsForUse):

Cilest

TheevaluationoftheclinicalsafetyofCilestwasbasedonthreePhase3studiesconducted:acontrolled2-cellsafety

andefficacycomparisonstudy(A-3437),acontrolled2-cellcomparisonstudyofcoagulationeffects(D83-001)andan

openefficacyandsafetystudy(C82-083).All3studiesweretwoyear(24cycles)studiesandcumulativelyevaluateda

totalof1647womenand22,237cycles.Informationonundesirableadversereactionsfromthesecombinedstudiesis

presentedbelow.

Headachewasthemostfrequentlyreportedandonlyverycommonlyreportedadversereaction(30%).

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Listedbelowareadversereactionsthathavebeenassociatedwiththeuseofhormonalcontraceptives:

CardiovascularSystem:cerebrovascularaccidents,arterialthromboembolism,myocardialinfarction,hypertension

Neoplasms:benignlivertumors,malignanthepatictumors

Hepatobiliary:intrahepaticcholestasis,cholelithiasis,cholestaticjaundice,Budd-Chiarisyndrome

GenitalTract:absenceofwithdrawalbleeding,changeinmenstrualflow,increaseinsizeofuterinefibromyoma,

increaseincervicalerosionandsecretion,temporaryinfertilityafterdiscontinuationoftreatment,pre-menstrual

syndrome

Breast:diminutioninlactationwhengivenimmediatelypost-partum

Skinandsubcutaneoustissue:seborrhea,hypertrichosis,pemphigoid(herpesgestationis),

4.9Overdose

Overdosagemaycausenausea,vomitingandwithdrawalbleedinginfemales.Seriousilleffectshavenotbeenreported

followinglargedosesoforalcontraceptivesinchildren.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCCode:G03AA11

Althoughthepharmacologicalactionsofestrogensandprogestogenswhicharepresentinallcombinedoral

contraceptivesarelargelyunderstood,theexactmechanismoftheiractionsotherthansuppressionofovulationremains

controversial.

Cilestactsthroughthemechanismofgonadotropinsuppressionbytheestrogenicandprogestationalactionsofethinyl

estradiolandnorelgestromin.Theprimarymechanismofactionisinhibitionofovulation,butalterationstothecervical

ADVERSEREACTIONSREPORTEDINCLINICALTRIALSOFCILEST

OrganSystem Commonadverse

event(>1/100,<1/10) Uncommonadverseevents

(>1/1000,<1/100) Rareadverseevents

(>1/10000,<1/1000)

Cardiovascular Edema Slightriseofbloodpressure,

hypertension Myocardialinfarction,

deepvenous

thrombosis,pulmonary

embolismandother

embolisms

Neoplasms Cervicalcancer,breast

cancer

GenitalTract Intermenstrual

bleeding,spotting,

amenorrhea,vaginal

candidiasis

Breast Tenderness Galactorrhea,pain,

enlargement

Gastro-intestinaltract Abdominalcramps,

bloating Nausea,vomitingcolitis

Skin Acne,rash Alopecia,hirsuitism,chloasma Erythema(nodosum,

multiforme)

Migraine,mood

changes,depression Irritability,changesinlibido

Metabolic Fluidretention,changes

inbodyweight

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Receptorandsexhormonebindingglobulin(SHBG)bindingstudies,aswellasstudiesinanimalsandhumans,have

shownthatbothnorgestimate(NGM)andnorelgestromin,themajorserummetaboliteofnorgestimatefollowingoral

administration,exhibitshighprogestationalactivitywithminimalintrinsicandrogenicity,whichillustratestheselective

actionofCilest.Norgestimate,incombinationwithethinylestradiol,doesnotcounteracttheestrogen-induced

increasesinSHBG,resultinginlowerlevelsoffreetestosteroneinserumcomparedtobaseline.

5.2Pharmacokineticproperties

Absorption:Norgestimateandethinylestradiolarerapidlyabsorbedfollowingoraladministration.Followingsingleor

multiple(threecycles)administrationofCilest,serumconcentrationsofnorgestimateremainbelowthequantitation

limitoftheassay(0.1ng/mL)duetorapidmetabolism(seeMetabolismbelow).Itsmetabolites,norelgestrominand

norgestrel,arefoundinmeasurableconcentrationsincirculation,reachingmaximalserumlevelsapproximately1.5

hourspost-dose.Exposuretonorelgestrominisproportionaltodosefollowingnorgestimatedosesof0.180to0.250

mg.Ethinylestradiolserumconcentrationsaremeasurablewithin0.5hoursofdosing,reachingpeaklevels

approximately1.2hourspost-dose.

Distribution:Norelgestrominandnorgestrelarehighlybound(>97%)toserumproteins.norelgestrominisboundto

albuminbutnottoSHBG,whilenorgestrelisboundprimarilytoSHBGandtoamuchlesserextenttoalbumin.Ethinyl

estradiolisextensivelyboundtoserum

albumin.

StudieshaveshownthatthelackofbindingofnorelgestromintoSHBGisuniquewhencomparedtoother

progestogensinoralcontraceptivesandplaysakeyroleinenhancingitsbiologicalactivity.Incontrast,norgestrel

formedfromnorgestimateislargelyboundtoSHBG,whichlimitsitsbiologicactivity.Thesefindingstogetherwith

theselectivityofnorelgestrominfortheprogesteronereceptorindicatethatthismetabolitemayexplaintheunique

clinicalprofileofnorgestimate.

Metabolism:Norgestimateisrapidlymetabolizedbyfirst-pass(intestinaland/orhepatic)mechanismsto

norelgestromin(peakserumconcentrationsobservedwithin2hours)andnorgestrel,bothofwhichare

pharmacologicallyactiveprogestogens.Ethinylestradiolismetabolizedtovarioushydroxylatedmetabolitesandtheir

glucuronideandsulfateconjugates.

Elimination:Bothnorelgestrominandnorgestrel,andethinylestradiolaresubsequentlymetabolizedandtheir

metabolitesareeliminatedbyrenalandfecalpathways.Eliminationhalf-lifevaluesatsteady-statewere10to15hours

forethinylestradiol,24.9hoursfornorelgestrominand45hoursfornorgestrel.Followingadministrationof 14

norgestimate,47%oftheadministeredradioactivitywaseliminatedintheurineand37%inthefeces.

Steady-StatePharmacokinetics:Followingadministrationof0.250mg/0.035mgethinylestradiol,thedaily

exposure(meanAUC

0-24h )atsteady-state,basedonnon-SHBGboundserumlevels,was18.1hng/mLfor

norelgestrominand3.64hng/mLfornorgestrel.Followingoraladministrationof0.150mglevonorgestrel/0.030mg

ethinylestradiol,meandailyexposureatsteady-state,basedonnon-SHBGboundserumlevels,was18.9hng/mLfor

norgestrel.Theexposuretonorgestrelfollowingadministrationof0.250mg/0.035mgethinylestradiol,correspondsto

theexposureafteralevonorgestreldoseofapproximately30microgramsincombinationwithethinylestradiol.

5.3Preclinicalsafetydata

Acomprehensivesetoftoxicitystudieshavebeenconductedoneachofthecomponentsindividuallyandin

combination.Thesestudiesincludesingledosestudiesinmultiplespecies,repeateddosestudiesuptotwoyearsinthe

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ResultsshowthattheacuteoralLD

ofnorgestimate(NGM)plusethinylestradiol(EE)inratsisgreaterthan5g/kg,

indicatingaveryloworderofacutetoxicityandawidemarginofsafety.Repeateddosestudiesingenerallaboratory

animals(rats,dogs,monkeys),atNGM+EEratiosofupto10:1insubchronic(3-monthstudies,atdosesof~1000

timestheclinicaldose)andratiosofupto5:1inchronic(2-yearstudies,atdosesof~100timestheclinicaldose)

studies,showedsomewhatsimilarresults,suchasreductionofestruscyclesormenstruation,decreaseduterineand

ovarianweights,increasedliverandpituitaryweights,decreasedserumcholesterollevelsanderythrocyticparameters,

withmostoftheprimarytreatmentrelatedeffectsjudgedtobeduetoanexaggeratedpharmacologyactionofNGM+

EE,orgeneralageingphenomenon.

Inlong-termstudies,increasedincidenceofmammaryneoplasm'sandlenticularopacitiesinrats(2-yearstudyatdoses

upto600timestheclinicaldose)wasconsideredahighdoseeffectandprobablynotrelevantatoptimally

pharmacologicaldoselevels.Inthe7-yeardogstudy,atdosesupto25timestheclinicaldose,leiomyomas(fibroids)

wereobservedataslightlygreaterincidenceinthehigh-dosegroup.Thesetumoursarethemostfrequentoccurring

spontaneousneoplasm'softhereproductivetractinfemaledogsandareapparentlyduetoestrogenoverloadingandare

unlikelytooccuratoptimallypharmacologicaldoses.Anon-doserelatedlenticularopacitieswerealsoobservedinthe

7-yeardogstudy.Althoughlenticularopacitiesisanormalobservationindogs,itgenerallyhasalongerlatencyperiod.

Neoplasm'sobservedinthe10-yearmonkeystudy(atdosesupto50timestheclinicaldose),aresingleoccurrences

andgenerallyindifferentorgans,withsimilarspontaneousoccurrencesbeingreportedinthescientificliterature.

Inreproductionstudies,noted,doserelatedeffectsonfertility,maternalandfetalparameters,andlactationareexpected

responsestothepharmacologicalactionsofthisclassofanti-fertilitycompoundsandwereobservedatdoselevels

withinthepharmacodynamicrange.Embryolethalityandskeletalvariationsinratswasobservedwithnoincreasein

extragenitalanomalies.NGM+EEisnotconsideredateratogen.NGM+EE,NGManditsprimarymetabolite

norelgestromin(NGMN),haveshownnoindicationofanymutagenicpotential.

Inconclusion,thecombinationofnorgestimate(NGM)andethinylestradiol(EE)inlaboratoryanimalshasshown

somepreclinicaleffects,whichwereobservedatexposuresconsideredsufficientlyinexcessofthemaximumhuman

exposure,orweretheresultofnormalageingprocessorfromanexaggerationofpharmacologicaleffectsathigherthan

therapeuticdosesindicatinglittlerelevancetoclinicaluse.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactose(anhydrous)

Magnesiumstearate

Pregelatinisedstarch

FD&CBlueNo2Lake

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

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6.5Natureandcontentsofcontainer

Cartoncontaining1PVC/foilblisterstripsof21tabletseachinanoverlabelledoutercarton.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA465/217/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:3 rd

July2009

10DATEOFREVISIONOFTHETEXT

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